1. Field of Invention
The present invention relates to a composition for prevention or improvement of medical symptoms caused by leucotriene B4 (LTB.sub.4), comprising as an effective ingredient an omega 9 series unsaturated fatty acid. More specifically, the present invention relates a composition for prevention or improvement of inflammation, especially chronic inflammation such as rheumatoid arthritis, or allergy, comprising at least one effective ingredient selected from the group consisting of 6,9-octadecadienoic acid, 8,11-eicosadienoic acid and 5,8,11-eicosatrienoic acid.
2. Related Art
Inflammation is a defense reaction of organisms caused by a physical or chemical stimulation, immunological phenomena involving antibodies, immune complex, degradation products of complements, or the like. During the inflammation, characteristic phenomena occur including expansion and perforation of microvessels, leak of blood components into spaces between tissues, migration of leucocytes to an inflammatory tissue, and the like, resulting in symptoms such as erythema, edema, hyperalgesia, ache etc. In a process of inflammation, various pharmacologically active substances are locally formed and liberated, and mediate inflammatory reactions. These substances are called chemical mediators of inflammation, and include plasmakinins such as bradykinin, serotonin, histamines and the like, prostaglandin (PG), leucotriene (LT), various leucocyte migration enhancement factors, and the like.
Allergy is a condition wherein reaction harmful to an organism, such as destruction and abnormal reaction of tissue results from an immune response. In the allergy process, it is known that an allergen invades an organism and reacts with IgE antibody fixed to mast cell or basophilic leukocyte resulting in liberation of a chemical transmitter such as histamines, leucotriene (LT), eosinophilic migration enhancement factor, neutrophilic migration enhancement factor, and the like, providing cell infiltration, destruction of tissues, contraction of smooth muscle, stimulation of vascular permeability, stimulation of mucous secretion etc.
Generally, although anti-inflammatory drugs are used for inhibiting inflammatory symptoms and alleviating destruction of tissues, in the broad sense, they include allergic reaction inhibitory drugs (anti-allergic drugs). Currently available anti-inflammatory drugs are classified as steroidal anti-inflammatory drugs (adrenocortical hormones) and non-steroidal anti-inflammatory drugs. Although the steroidal anti-inflammatory drugs provide strong anti-inflammatory action, they also exhibit strong side-effects, and therefore determination of termination of and method for administration is difficult. On the other hand, although acidic non-steroidal anti-inflammatory drugs such as aspirin, indomethacin etc. exhibit anti-inflammatory action by lowering cycloxygenase activity and inhibiting PG synthesis, and are used as frequently as antibiotics and lanking after steroidal drugs, they provide side effects such as gastro-intestinal injurys, nephrotoxicity, hemopoietic disorders, and therefore their use is very limited.
A more recent approach to the moderation of inflammatory and hypersensitivity responses has focused on blocking the action of arachidonic acid metabolites (including the prostaglandins), lipoxygenases and the leukotrienes. The leukotrienes (LT) metabolites are formed by oxygenation of a lipoxygenase (5-hydroperoxytetraenoic acid (5-HPETE)) which is formed by the specific oxygenation of the C-5 position of arachidonic acid. The first leukotriene formed in the metabolic pathway is the unstable epoxide intermediate leukotriene A.sub.4 (LTA.sub.4) which is the precursor to the family of peptide-leukotrienes, the first in the pathway being LTC.sub.4 which is formed by glutathione addition. LTC.sub.4 is transformed subsequently into LTD.sub.4 and LTE.sub.4 by successive elimination of a glutamyl and glycine residue. The peptido-leukotrienes primarily act on smooth muscle and other cells having contractile capacity, as well as playing a key role in hypersensitivity reactions. In addition, the peptido-leukotrienes are spasmogens, increase vascular permeability, activate airway smooth muscle, stimulate mucous secretion and are involved with the pathogenesis of certain inflammatory diseases such as bronchitis, ectopic and atopic eczema and psoriasis. Leukotrienes appear to be involved in the pathogenesis of asthma such as allergic pulmonary disorders of asthma, hay fever and allergic rhinitis. In addition, LTC.sub.4, LTD.sub.4 and LTE.sub.4 may also decrease blood pressure by an action on the heart, because they reduce myocardial contractility and coronary blood flow.
Another family of leukotrienes, the LTB.sub.4, is derived from LTA.sub.4 by hydrolase-catalyzed addition of water. This 5,12-dihydroxy derivative, causes adhesion and chemotactic movement of leukocytes, stimulates aggregation, enzyme release and generation of superoxide in neutrophils. Additionally, LTB.sub.4 is a potent chemotactic and chemokinetic agent for eosinophils, macrophages and monocytes, stimulates suppressor T lymphocytes and enhances natural cytotoxic cell activity. LTB.sub.4 is also a potent (indirect) bronchoconstrictor but in contrast to the peptido-leukotrienes C.sub.4, D.sub.4 and E.sub.4 does not appreciably stimulate mucous production and induce edema of the airways by increasing vascular permeability.
It has been suggested that compounds antagonizing LTB.sub.4 activity may be valuable in the treatment of inflammatory diseases caused by tissue degrading enzymes and reactive chemicals liberated by tissue-infiltrating and aggregating polymorphonuclear leukocytes.
For example, PCT Japanese National Publication No. 6-502164 describes that novel monocyclic or bicyclic aryl compounds are selectively antagonistic to LTB.sub.4 and are useful for treatment of rheumatoid arthritis, gout, psoriasis and inflammatory bowel disease. Japanese Unexamined Patent Publication (Kokai) No. 4-244023 describes that .omega.6 series unsaturated fatty acids such as dihome-.gamma.-linolenic acid are useful for treatment of arrhythmia, acute myocardial infarction etc. by inhibiting production of LTB.sub.4. Japanese Unexamined Patent Publication No. 5-310668 describes that a novel leucine derivative has an inhibitory action to LTA.sub.4 hydrolase and are useful for treatment and prophylaxis of allergic diseases such as bronchial asthma, various inflammatory diseases, ischemia-reperfusion disorders. Japanese Unexamined Patent Publication (Kokai) No. 1-190656 discloses that novel leucotriene B.sub.3 dimethyl amide has an antagonistic action to LTB.sub.4 and is useful as anti-inflammatory drug, anti-rheumatic drug and gout-treatment drug.
On the other hand, it is known that 8,11-cis-eicosadienoic acid and 5,8,11-cis-eicosatrienoic acid (mead acid), which are omega 9 series fatty acids, are produced in animal tissues deficient in essential fatty acids. J. Biolog Chem. Vol. 259, No. 19, pp.11784-11789 (1984) discloses that in neutrophile of rat fed on essential fatty acid deficient feed, mead acid was detected, which was not detected in rat fed on normal feed, and an amount of LTB.sub.4 decreased. However, this phenomenon is under a specific condition of essential fatty acid deficiency, and it is not clear whether mead acid alone inhibits the production of LTB.sub.4 and exhibits anti-inflammatory or anti-allergic action.
In addition, Japanese Unexamined Patent Publication No. 62-129241 describes that a particular ester or amide of 5,8,11-eicosatriynoic acid inhibits the metabolism of arachidonic acid caused by cyclooxygenase and lypoxygenase. U.S. Pat. No. 4,432,906 describes that 10,10-dimethyl-5,8,11-eicosatrienoic acid and 10-methyl-5,8,11-eicosatrienoic acid are useful as anti-allergic drug and anti-asthma drug because they do not inhibit the synthesis of PG, but inhibit the synthesis of SRS-A. U.S. Pat. No. 4,434,101 describes that 7,7-dimethyl-5,8-eicosadienoic acid and 7-methyl-5,8-eicosadienoic acid are useful as anti-allergic agent and anti-asthma drug because they do not inhibit the synthesis of PG and inhibit the synthesis of SRS-A. However, it is not clear whether or not omega 9 series unsaturated fatty acid such as mead acid has LTB.sub.4 production inhibitory action and is useful as prophylactic or improving drugs for inflammation, especially chronic inflammation such as rheumatoid arthritis, and allergy.
Arthritic rheumatism is a chronic polyinflammatory disease, and in the serum and synovial fluid of rheumatoid arthritis patients rheumatoid factor which is an autoantibody reactive with immunoglobulin IgG is detected. Because of the presence of the rheumatoid factor, it is considered that the rheumatoid arthritis involves immune disorder. However, the cause of the disease is not known. In the treatment of rheumatoid arthritis, non-steroidal anti-inflammatory drugs are used for symptomatic therapy through the entire disease process.